Impaired arm and hand function is one of the most disabling and most common consequences of stroke. Approximately 75% of the over 795,000 strokes that occur annually in the Unites States cause some degree of upper limb paralysis acutely. By 6 months post-stroke an estimated 65% of patients still cannot incorporate the impaired arm and hand into their daily activities, and nearly one third have chronic loss of upper limb function, which is often characterized by inability to extend the arm and open the hand. While the impact of upper limb impairments on disability and health is great, there are relatively few rehabilitation interventions designed to restore function to the impaired upper limb. Therefore, our long-term objective is to develop rehabilitation therapies for the paretic upper limb that are optimized for effectiveness, applicability, and implementation. Contralaterally Controlled Functional Electrical Stimulation (CCFES) is an innovative neuromuscular electrical stimulation (NMES) treatment for improving the recovery of hand function after stroke. CCFES stimulates the paretic hand to open in proportion to the degree of volitional opening of the contralateral unimpaired hand. This enables the stroke survivor to perform active repetitive hand opening exercises, hand motor-control tasks, and functional tasks with the paretic hand. In this study, we add stimulation of elbow extensors controlled by the contralateral elbow in order to improve reach as well as hand opening. The purpose of this study is to optimize CCFES by adding stimulated elbow extension, increasing and evaluating the effect of treatment duration, and estimating the best time after stroke to begin treatment. The specific aims include: 1) estimating the effect of Arm+Hand CCFES on upper limb motor impairment and activity limitation, 2) estimating the effect of treatment duration, 3) defining the relationship between treatment effect and time elapsed between stroke onset and start of treatment. One hundred eight (108) stroke survivors with acute/subacute (&#8804; 6 months post-stroke) upper limb hemiplegia will be randomly assigned in equal proportions to receive either 6, 9, or 12 weeks of Arm+Hand CCFES or 12 weeks of cyclic NMES, which is an intervention that stimulates the elbow and hand to extend, but with pre-set timing and intensity. Upper limb impairment and activity limitation will be assessed at baseline, 6, 9, 12, 20, 28, and 36 weeks. By optimizing the CCFES treatment for acute stroke survivors, its therapeutic effect will be maximized and the optimum treatment duration and timeframe to start treatment will be estimated. This information is critical for the design of a large-scale efficacy trial of Arm+Hand CCFES, and will serve to accelerate the development and ultimately the dissemination of a new treatment for reducing post-stroke disability. PUBLIC HEALTH RELEVANCE: There is a need for more effective motor rehabilitation interventions for individuals who have become disabled by stroke. This study is an important step toward the development of a new treatment that may be more effective in facilitating lasting motor recovery, more widely applicable to a broader range of stroke survivors, and more readily implemented than existing stroke rehabilitation techniques. As more effective stroke rehabilitation therapies are developed and administered during the acute recovery phase, the prevalence of chronic post-stroke disability may be decreased.